This renewal continues efforts toward establishing diffusion-weighted MRI (DWI) as a quantitative imaging metric for cancer patients. Based upon our progress to date, this renewal effort will be advanced through three Specific Aims along with strategic collaborations within the NCI Quantitative Imaging Network (QIN), Imbio, LLC (industrial partner) and the National Institute of Standards and Technology (NIST). (Aim 1) Development of a standardized platform for diffusion analysis and validation of DWI metrics for quantification of tumor diffusion values will be accomplished through establishment of histogram and voxel-based metrics. (Aim 2) In collaboration with NIST, development of the next generation DWI phantom using in-situ thermometry for precise diffusion measurements over the full clinically-relevant ADC range to generate quantitative quality assurance and system performance metrics across diverse scanner platforms. (Aim 3) Based on measured system characteristics, implementation of retrospective correction of DW nonlinearity errors in multi-center trials is possible. This research effort will address major hurdles in establishing DWI for therapeutic response assessment to improve clinical management of cancer patients. We will develop and rigorously test a medical imaging platform allowing for a standardized implementation and clinical validation of advanced DWI analytical techniques for quantification of tumor diffusion values across multiple MRI systems. We will also continue the success of our widely-adopted ice water DWI phantom with the development of a next-generation DWI phantom platform that will provide quantitative diffusion measurements over the full tissue range of diffusion values. Finally, we will provide a strategy for resolving a major source of technical variability in DWI related to instrumental bias from differences in MRI gradient systems through the development of system-specific correction tools. The renewal of our QIN project will provide advanced analytical and quality assurance support to clinical trials including I-SPY2 (investigation of serial studies to predict your therapeutic response with imaging and molecular analysis, ACRIN 6698, and ACRIN 6702. Success of this endeavor will significantly advance the clinical management of cancer patients ultimately improving outcomes.